tbuckley/cabot-search huggingface dataset:
Characterization of the depsidone gene cluster reveals etherification, decarboxylation and multiple halogenations as tailoring steps in depsidone assembly
Authors: Jiafan Yang, Zhenbin Zhou, Yingying Chen, Yongxiang Song, Jianhua Ju
Journal: Acta Pharmaceutica Sinica B (2023)

Depsides and depsidones have attracted attention for biosynthetic studies due to their broad biological activities and structural diversity. Previous structure‒activity relationships indicated that triple halogenated depsidones display the best anti-pathogenic activity. However, the gene cluster and the tailoring steps responsible for halogenated depsidone nornidulin (3) remain enigmatic. In this study, we disclosed the complete biosynthetic pathway of the halogenated depsidone through in vivo gene disruption, heterologous expression and in vitro biochemical experiments. We demonstrated an unusual depside skeleton biosynthesis process mediated by both highly-reducing polyketide synthase and non-reducing polyketide synthase, which is distinct from the common depside skeleton biosynthesis. This skeleton was subsequently modified by two in-cluster enzymes DepG and DepF for the ether bond formation and decarboxylation, respectively. In addition, the decarboxylase DepF exhibited substrate promiscuity for different scaffold substrates. Finally, and interestingly, we discovered a halogenase encoded remotely from the biosynthetic gene cluster, which catalyzes triple-halogenation to produce the active end product nornidulin (3). These discoveries provide new insights for further understanding the biosynthesis of depsidones and their derivatives.
mutscan—a flexible R package for efficient end-to-end analysis of multiplexed assays of variant effect data
Authors: Charlotte Soneson, Alexandra M. Bendel, Guillaume Diss, Michael B. Stadler
Journal: Genome biology (2023)

Abstract Multiplexed assays of variant effect (MAVE) experimentally measure the effect of large numbers of sequence variants by selective enrichment of sequences with desirable properties followed by quantification by sequencing. mutscan is an R package for flexible analysis of such experiments, covering the entire workflow from raw reads up to statistical analysis and visualization. The core components are implemented in C++ for efficiency. Various experimental designs are supported, including single or paired reads with optional unique molecular identifiers. To find variants with changed relative abundance, mutscan employs established statistical models provided in the edgeR and limma packages. mutscan is available from https://github.com/fmicompbio/mutscan .
A survey of mapping algorithms in the long-reads era
Authors: Kristoffer Sahlin, Thomas Baudeau, Bastien Cazaux, Camille Marchet
Journal: Genome biology (2023)

It has been over a decade since the first publication of a method dedicated entirely to mapping long-reads. The distinctive characteristics of long reads resulted in methods moving from the seed-and-extend framework used for short reads to a seed-and-chain framework due to the seed abundance in each read. The main novelties are based on alternative seed constructs or chaining formulations. Dozens of tools now exist, whose heuristics have evolved considerably. We provide an overview of the methods used in long-read mappers. Since they are driven by implementation-specific parameters, we develop an original visualization tool to understand the parameter settings ( http://bcazaux.polytech-lille.net/Minimap2/ ).
Evaluation of the Cherokee Nation Hepatitis C Virus Elimination Program — Cherokee Nation, Oklahoma, 2015–2020
Authors: Whitney Essex, Molly Feder, Jorge Mera
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

Approximately 2.4 million persons in the United States have hepatitis C virus (HCV) infection, and 66,700 acute HCV infection cases were estimated for 2020 (1,2). American Indian or Alaska Native (AI/AN) persons are disproportionately affected by HCV infection and experienced the highest rates of acute HCV infection (2.1 cases per 100,000 persons) and HCV-associated mortality (10.17 per 100,000 persons) in the United States during 2020 (1). During 2015, Cherokee Nation Health Services (CNHS) in Oklahoma implemented an HCV elimination program, which includes universal HCV screening, primary HCV workforce expansion, and harm reduction services (3). To assess progress 5 years after program initiation, CNHS analyzed deidentified health record data. During November 1, 2015-October 31, 2020, a total of 1,423 persons received a diagnosis of HCV infection. Among these persons, 1,227 (86.2%) were linked to HCV care, and 871 (61.2%) initiated HCV treatment; 702 (49.3%) returned for their 12-week post treatment completion visit, at which time 698 (49.1%) had achieved laboratory-confirmed sustained virologic response (SVR), defined as undetectable HCV RNA at ≥12 weeks after completion of treatment (SVR12). Although CNHS has linked the majority of persons diagnosed with HCV infection to care, and those who returned for the SVR12 visit had high cure rates (99.4%), treatment initiation was lower than expected. Future activities should prioritize addressing gaps in treatment initiation after linkage to care and confirmation of hepatitis C cure with SVR12 testing.
Community Water Fluoridation Levels To Promote Effectiveness and Safety in Oral Health — United States, 2016–2021
Authors: Theresa J. Boehmer, Srdjan Lesaja, Lorena Espinoza, Chandresh N. Ladva
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

Drinking water fluoridated at the level recommended by the U.S. Public Health Service (USPHS) reduces dental caries (cavities) by approximately 25% in children and adults (1). USPHS recommends fluoride levels to achieve oral health benefits and minimize risks associated with excess fluoride exposure. To provide the benefits of community water fluoridation, water systems should target a level of 0.7 mg/L and maintain levels ≥0.6 mg/L (2). The Environmental Protection Agency (EPA) sets a safety standard at 2.0 mg/L to prevent mild or moderate dental fluorosis, a condition that causes changes in the appearance of tooth enamel caused by hypermineralization resulting from excess fluoride intake during tooth-forming years (i.e., before age 8 years). During 2016-2021, fluoride measurements for 16.3% of population-weighted monthly fluoride measurements (person-months) reported by community water systems to CDC's Water Fluoridation Reporting System (WFRS) were <0.6 mg/L; only 0.01% of person-months exceeded 2.0 mg/L. More than 80% of population-weighted fluoride measurements from community water systems reporting to WFRS were above 0.6 mg/L. Although 0.7 mg/L is the recommended optimal level, ≥0.6 mg/L is still effective for the prevention of caries. A total of 4,080 community water systems safely fluoridated water 99.99% of the time with levels below the secondary safety standard of 2.0 mg/L. Water systems are encouraged to work with their state programs to report their fluoride data into WFRS and meet USPHS recommendations to provide the full benefit of fluoridation for caries prevention.
Anti–miR-93-5p therapy prolongs sepsis survival by restoring the peripheral immune response
Authors: Mihnea P. Dragomir, Enrique Fuentes-Mattei, Melanie Winkle, Keishi Okubo, Recep Bayraktar, Erik Knutsen, Aiham Qdaisat, Meng Chen, Yongfeng Li, Masayoshi Shimizu, Lan Pang, Kevin Liu, Xiuping Liu, Simone Anfossi, Huanyu Zhang, Ines Koch, Anh M. Tran, Swati Mohapatra, Anh Ton, Mecit Kaplan, Matthew W. Anderson, Spencer J. Rothfuss, Robert Silasi, Ravi S. Keshari, Manuela Ferracin, Cristina Ivan, Cristian Rodriguez-Aguayo, Gabriel Lopez-Berestein, Constantin Georgescu, Pinaki P. Banerjee, Rafet Basar, Ziyi Li, David Horst, Catalin Vasilescu, Maria Teresa S. Bertilaccio, Katayoun Rezvani, Florea Lupu, Sai-Ching Yeung, George A. Calin
Journal: Journal of Clinical Investigation (2023)

Sepsis remains a leading cause of death for humans and currently has no pathogenesis-specific therapy. Hampered progress is partly due to a lack of insight into deep mechanistic processes. In the past decade, deciphering the functions of small noncoding miRNAs in sepsis pathogenesis became a dynamic research topic. To screen for new miRNA targets for sepsis therapeutics, we used samples for miRNA array analysis of PBMCs from patients with sepsis and control individuals, blood samples from 2 cohorts of patients with sepsis, and multiple animal models: mouse cecum ligation puncture-induced (CLP-induced) sepsis, mouse viral miRNA challenge, and baboon Gram+ and Gram- sepsis models. miR-93-5p met the criteria for a therapeutic target, as it was overexpressed in baboons that died early after induction of sepsis, was downregulated in patients who survived after sepsis, and correlated with negative clinical prognosticators for sepsis. Therapeutically, inhibition of miR-93-5p prolonged the overall survival of mice with CLP-induced sepsis, with a stronger effect in older mice. Mechanistically, anti-miR-93-5p therapy reduced inflammatory monocytes and increased circulating effector memory T cells, especially the CD4+ subset. AGO2 IP in miR-93-KO T cells identified important regulatory receptors, such as CD28, as direct miR-93-5p target genes. In conclusion, miR-93-5p is a potential therapeutic target in sepsis through the regulation of both innate and adaptive immunity, with possibly a greater benefit for elderly patients than for young patients.
<i>Notes from the Field:</i> Update on Pediatric Intracranial Infections — 19 States and the District of Columbia, January 2016–March 2023
Authors: Emma K. Accorsi, Matt Hall, Adam L. Hersh, Samir S. Shah, Stephanie J. Schrag, Adam L. Cohen
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

In May 2022, CDC began an investigation of a possible increase in pediatric intracranial infections, particularly those caused by Streptococcus bacteria, during the preceding year (1).January 2016-May 2022 data from a large, geographically diverse network of children's hospitals showed altered patterns in pediatric intracranial infections after the onset of the COVID-19 pandemic (1).In this update, extended hospitalization data through March 2023 from 37 hospitals in 19 states and the District of Columbia showed a higher-than-expected number of pediatric intracranial infections beginning in August 2021, with a large peak during winter 2022-2023.Pediatric intracranial infections are recognized as a severe complication of viral respiratory infection and sinusitis (2), and the winter 2022-2023 peak coincided with spikes in respiratory virus circulation* , † (3,4).Even during this peak, intracranial infections remained rare.CDC continues to track trends in pediatric intracranial infections and recommends that all persons aged ≤18 years remain current with recommended vaccinations, including influenza and COVID-19.§ To characterize national trends in pediatric intracranial infections, CDC analyzed pediatric hospitalizations for brain abscesses, epidural empyemas, and subdural empyemas reported to the Children's Hospital Association's Pediatric Health Information System (PHIS) by 37 tertiary referral children's hospitals in 19 states and the District of Columbia.The included hospitals consistently reported to PHIS during January 1, 2016-March 31, 2023 (the most recent data available when the analysis was performed).¶ All inpatient encounters with persons aged ≤18 years that had a primary or secondary International Classification of Diseases, Tenth Revision, Clinical Modification discharge diagnosis code G06.0 (intracranial abscess and granuloma) or G06.2 (extradural and subdural abscess, unspecified) during the study period were included.Because the study period was extended from * https://www.cdc.gov/rsv/research/rsv-net/dashboard.html† https://gis.cdc.gov/GRASP/Fluview/PedFluDeath.html§ https://www.cdc.gov/vaccines/schedules/hcp/imz/child-adolescent.html¶ Population denominators were not available; therefore, analysis was limited to hospitals that reported data for each month during the study period.* The median and maximum number of cases per month during 2016-2019, by U.S. Census Bureau region.† Data from 37 children's hospitals in 19 states and the District of Columbia.The number of hospitals that provided data in each U.S. Census Bureau region were as follows: five (Northeast Region), 13 (Midwest Region), 11 (South Region), and eight (West Region).
Pervasive tandem duplications and convergent evolution shape coral genomes
Authors: Benjamin Noel, France Denoeud, Alice Rouan, Carol Buitrago-López, Laura Capasso, Julie Poulain, Emilie Boissin, Mélanie Pousse, Corinne Da Silva, Arnaud Couloux, Eric Armstrong, Quentin Carradec, Corinne Cruaud, Karine Labadie, Julie Lê-Hoang, Sylvie Tambutté, Valérie Barbe, Clémentine Moulin, Guillaume Bourdin, Guillaume Iwankow, Sarah Romac, Sylvain Agostini, Bernard Banaigs, Emmanuel Boss, Chris Bowler, Colomban de Vargas, Eric Douville, J. Michel Flores, Didier Forcioli, Paola Furla, Pierre E. Galand, Fabien Lombard, Stéphane Pesant, Stéphanie Reynaud, Matthew B. Sullivan, Shinichi Sunagawa, Olivier P. Thomas, Romain Troublé, Rebecca Vega Thurber, Denis Allemand, Serge Planes, Eric Gilson, Didier Zoccola, Patrick Wincker, Christian R. Voolstra, Jean-Marc Aury
Journal: Genome biology (2023)

Over the last decade, several coral genomes have been sequenced allowing a better understanding of these symbiotic organisms threatened by climate change. Scleractinian corals are reef builders and are central to coral reef ecosystems, providing habitat to a great diversity of species.In the frame of the Tara Pacific expedition, we assemble two coral genomes, Porites lobata and Pocillopora cf. effusa, with vastly improved contiguity that allows us to study the functional organization of these genomes. We annotate their gene catalog and report a relatively higher gene number than that found in other public coral genome sequences, 43,000 and 32,000 genes, respectively. This finding is explained by a high number of tandemly duplicated genes, accounting for almost a third of the predicted genes. We show that these duplicated genes originate from multiple and distinct duplication events throughout the coral lineage. They contribute to the amplification of gene families, mostly related to the immune system and disease resistance, which we suggest to be functionally linked to coral host resilience.At large, we show the importance of duplicated genes to inform the biology of reef-building corals and provide novel avenues to understand and screen for differences in stress resilience.
Small molecules targeting protein–protein interactions for cancer therapy
Authors: Defa Wu, Yang Li, Lang Zheng, Huan Xiao, Liang Ouyang, Guan Wang, Qiu Sun
Journal: Acta Pharmaceutica Sinica B (2023)

Protein-protein interactions (PPIs) are fundamental to many biological processes that play an important role in the occurrence and development of a variety of diseases. Targeting the interaction between tumour-related proteins with emerging small molecule drugs has become an attractive approach for treatment of human diseases, especially tumours. Encouragingly, selective PPI-based therapeutic agents have been rapidly advancing over the past decade, providing promising perspectives for novel therapies for patients with cancer. In this review we comprehensively clarify the discovery and development of small molecule modulators of PPIs from multiple aspects, focusing on PPIs in disease, drug design and discovery strategies, structure-activity relationships, inherent dilemmas, and future directions.
IMscin001 Part 2: a randomised phase III, open-label, multicentre study examining the pharmacokinetics, efficacy, immunogenicity, and safety of atezolizumab subcutaneous versus intravenous administration in previously treated locally advanced or metastatic non-small-cell lung cancer and pharmacokinetics comparison with other approved indications
Authors: M. Burotto, Z. Zvirbule, A. Mochalova, Y. Runglodvatana, L. Herraez-Baranda, S.N. Liu, P. Chan, E. Shearer-Kang, X. Liu, N. Tosti, J.A. Zanghi, B. Leutgeb, E. Felip
Journal: Annals of Oncology (2023)

Atezolizumab intravenous (IV) is approved for the treatment of various solid tumours. To improve treatment convenience and health care efficiencies, a coformulation of atezolizumab and recombinant human hyaluronidase PH20 was developed for subcutaneous (SC) use. Part 2 of IMscin001 (NCT03735121) was a randomised phase III, open-label, multicentre, noninferiority study comparing the drug exposure of atezolizumab SC with atezolizumab IV.
Profiling the metabolome of uterine fluid for early detection of ovarian cancer
Authors: Pan Wang, Jihong Ma, Wenjing Li, Qilong Wang, Yinan Xiao, Yuening Jiang, Xiaoyang Gu, Yu Wu, Suwei Dong, Hongyan Guo, Mo Li
Journal: Cell Reports Medicine (2023)

<h2>Summary</h2> Ovarian cancer (OC) causes high mortality in women because of ineffective biomarkers for early diagnosis. Here, we perform metabolomics analysis on an initial training set of uterine fluid from 96 gynecological patients. A seven-metabolite-marker panel consisting of vanillylmandelic acid, norepinephrine, phenylalanine, beta-alanine, tyrosine, 12-S-hydroxy-5,8,10-heptadecatrienoic acid, and crithmumdiol is established for detecting early-stage OC. The panel is further validated in an independent sample set from 123 patients, discriminating early OC from controls with an area under the curve (AUC) of 0.957 (95% confidence interval [CI], 0.894–1). Interestingly, we find elevated norepinephrine and decreased vanillylmandelic acid in most OC cells, resulting from excess 4-hydroxyestradiol that antagonizes the catabolism of norepinephrine by catechol-<i>O</i>-methyltransferase. Moreover, exposure to 4-hydroxyestradiol induces cellular DNA damage and genomic instability that could lead to tumorigenesis. Thus, this study not only reveals metabolic features in uterine fluid of gynecological patients but also establishes a noninvasive approach for the early diagnosis of OC.
Differences in the associations between psychoactive substance use and alexithymia: A series of Meta-analyses
Authors: Bernadette Kun, Pelin Alpay, Viktória Bodó, Ágnes Molnár, Andrea Horváth, Szilvia Karsai, Róza Sára Somlai, Zsofia K. Takacs, Gyöngyi Kökönyei
Journal: Clinical Psychology Review (2023)

The present meta-analytic study examined the association between alexithymia and psychoactive substance use. Studies published from 1988 to August 20, 2022 were identified by a systematic search and 168 eligible studies were included in five meta-analyses. Results showed that (1) the correlation between substance use and alexithymia is small but significant (r = 0.177); (2) substance users have substantially higher alexithymia than nonusers (g = 0.545); (3) alexithymic participants have significantly but slightly higher levels of substance use than non-alexithymics (g = 0.242); (4) substance users are significantly but only slightly more likely to be alexithymic than nonusers (OR = 2.392); and (5) alexithymic individuals are not more likely to be substance users than non-alexithymics. Larger effects were observed among samples diagnosed with substance use disorder (SUD), and the use of depressants, alcohol, opiates, and illicit stimulants had stronger relation to alexithymia. We found a tendency for a larger association with problematic use as compared to other indicators (e.g., frequency and duration) of substance use. Among the components of alexithymia, difficulties in identifying feelings has the strongest association with substance use. Our findings support clinical practice by suggesting the improvement of emotion regulation in SUD.
Genetically adjusted PSA levels for prostate cancer screening
Authors: Linda Kachuri, Thomas J. Hoffmann, Yu Jiang, Sonja I. Berndt, John P. Shelley, Kerry R. Schaffer, Mitchell J. Machiela, Neal D. Freedman, Wen-Yi Huang, Shengchao A. Li, Ryder Easterlin, Phyllis J. Goodman, Cathee Till, Ian Thompson, Hans Lilja, Stephen K. Van Den Eeden, Stephen J. Chanock, Christopher A. Haiman, David V. Conti, Robert J. Klein, Jonathan D. Mosley, Rebecca E. Graff, John S. Witte
Journal: Nature Medicine (2023)

Abstract Prostate-specific antigen (PSA) screening for prostate cancer remains controversial because it increases overdiagnosis and overtreatment of clinically insignificant tumors. Accounting for genetic determinants of constitutive, non-cancer-related PSA variation has potential to improve screening utility. In this study, we discovered 128 genome-wide significant associations ( P &lt; 5 × 10 −8 ) in a multi-ancestry meta-analysis of 95,768 men and developed a PSA polygenic score (PGS PSA ) that explains 9.61% of constitutive PSA variation. We found that, in men of European ancestry, using PGS-adjusted PSA would avoid up to 31% of negative prostate biopsies but also result in 12% fewer biopsies in patients with prostate cancer, mostly with Gleason score &lt;7 tumors. Genetically adjusted PSA was more predictive of aggressive prostate cancer (odds ratio (OR) = 3.44, P = 6.2 × 10 −14 , area under the curve (AUC) = 0.755) than unadjusted PSA (OR = 3.31, P = 1.1 × 10 −12 , AUC = 0.738) in 106 cases and 23,667 controls. Compared to a prostate cancer PGS alone (AUC = 0.712), including genetically adjusted PSA improved detection of aggressive disease (AUC = 0.786, P = 7.2 × 10 −4 ). Our findings highlight the potential utility of incorporating PGS for personalized biomarkers in prostate cancer screening.
Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer
Authors: Scott Haston, Estela Gonzalez-Gualda, Samir Morsli, Jianfeng Ge, Virinder Reen, Alexander Calderwood, Ilias Moutsopoulos, Leonidas Panousopoulos, Polina Deletic, Gabriela Carreno, Romain Guiho, Saba Manshaei, Jose Mario Gonzalez-Meljem, Hui Yuan Lim, Daniel J. Simpson, Jodie Birch, Husayn A. Pallikonda, Tamir Chandra, David Macias, Gary J. Doherty, Doris M. Rassl, Robert C. Rintoul, Massimo Signore, Irina Mohorianu, Arne N. Akbar, Jesús Gil, Daniel Muñoz-Espín, Juan Pedro Martinez-Barbera
Journal: Cancer Cell (2023)

The accumulation of senescent cells in the tumor microenvironment can drive tumorigenesis in a paracrine manner through the senescence-associated secretory phenotype (SASP). Using a new p16-FDR mouse line, we show that macrophages and endothelial cells are the predominant senescent cell types in murine KRAS-driven lung tumors. Through single cell transcriptomics, we identify a population of tumor-associated macrophages that express a unique array of pro-tumorigenic SASP factors and surface proteins and are also present in normal aged lungs. Genetic or senolytic ablation of senescent cells, or macrophage depletion, result in a significant decrease in tumor burden and increased survival in KRAS-driven lung cancer models. Moreover, we reveal the presence of macrophages with senescent features in human lung pre-malignant lesions, but not in adenocarcinomas. Taken together, our results have uncovered the important role of senescent macrophages in the initiation and progression of lung cancer, highlighting potential therapeutic avenues and cancer preventative strategies.